In Lupus (SLE) pathogenic (immune complex forming) IgG autoantibodies to nuclear autoantigens are produced with help from autoimmune T helper (Th), Th1 and Th17->TFH cells that also infiltrate kidneys. Although professional APCs are active in presenting autoantigens as disease progresses, it is important to identify which APCs are critical in the initial priming of autoimmune Th cells. Unexpectedly, we found that Lineage- (Lin-) CD117+ (c-Kit+) CX3CR1- (Cx-) cells in lupus splenocytes depleted of known APCs, were most proficient in processing and presenting nuclear autoantigen particles from apoptotic cells to induce autoimmune Th17 responses in lupus prone SNF1 and BL6.Sle mice. The autoimmune Th17 inducers in Lin-c- Kit+CX3CR1- splenocytes were c-Kit+CD41+CD151+ with properties of megakaryocyte (MkP) and/or bipotent megakaryocyte/erythroid progenitors (MEP) of bone marrow, hence the new APC are called M&M cells here. The M&M APC produce requisite cytokines for Th17, but they require contact for optimal Th17 induction upon nucleosome feeding, and can do so only before undergoing differentiation to become c-Kit-CD41+ cells. The M&M APC are increased up to 50 fold in mice and 10 fold in humans with lupus; and they accelerate lupus on transfer in vivo. By gene profiling, we have found select molecules expressed by M&M cells that might be targeted to prevent nuclear autoantigen presentation. Our major hypothesis is that a new category of APC, M&M cells, that efficiently present nuclear autoantigens to induce autoimmune Th17 without requiring Th17- polarizing conditions, use novel molecular pathways for their pathogenic function, and have signature molecules and growth factor requirements that could be targeted to block the autoimmunity generating process. We will accomplish following objectives in 3 years: Aim 1: Define molecular mechanisms by which M&M cells induce and expand Th17 cells; Target M&M signature molecules for lupus therapy; Define prevalence of M&M cells in other mouse models of lupus; Determine if they can break tolerance in normal mice, inducing Th17 skewing in response to foreign and self antigens; and characterize M&M's role in Human lupus. Aim 2: Study the impact of M&M cells on B cell tolerance and autoimmunity. The studies will substantially advance understanding of lupus pathogenesis and Th17 differentiation biology by characterizing a novel category of APC, determining whether these cells can be a new biomarker for lupus, or a target for lupus therapy by targeting/blocking the initial steps in the generation of autoimmunity. PUBLIC HEALTH RELEVANCE: Systemic Lupus Erythematosus (SLE or lupus), like rheumatoid arthritis, is a major autoimmune disease affecting more commonly women of child bearing age. Lupus patients produce pathogenic (disease causing) antibodies that form immune complexes and bind to normal tissue constituents. This causes severe inflammation and damage to kidneys, blood cells, joints, skin, blood vessels and brain. Although a special population of autoimmune T helper (Th1 and Th17) cells is essential for driving the B cells of lupus to produce pathogenic autoantibodies, the exact cause of lupus is unknown. In this proposal, we will determine how a novel antigen-presenting cell (APC) population initiates breakdown of tolerance to nuclear antigens to induce pathogenic T helper responses in lupus, and how this priming step can be blocked. Overall, understanding molecular and functional mechanism/s of the unusual and potent APC will be of therapeutic value in a broad spectrum of immune mediated diseases in addition to Lupus, such as, Rheumatoid arthritis, Crohn's disease, Psoriasis Multiple Sclerosis, and Autoimmune Diabetes.